Oncogenic Effects of High MAPK Activity in Colorectal Cancer Mark Progenitor Cells and Persist Irrespective of RAS Mutations

Blaj, Cristina; Schmidt, Éva; Lamprecht, Sebastian; Hermeking, Heiko; Jung, Andreas; Kirchner, Thomas; Horst, David

doi:10.1158/0008-5472.can-16-2821

Cited by 62 publications

(60 citation statements)

References 42 publications

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“…LAMC2 has previously been shown to promote EMT and invasion in an in vivo model of lung adenocarcinoma (Moon et al, 2015). It has also been shown that colorectal cancer with high MAPK activity express heightened levels of LAMC2, supporting our proteomic results that show reversal upon MEK inhibition (Blaj et al, 2017). PODXL had increased expression in all six mutant cell lines, and has been implicated in increasing the aggressiveness of breast and prostate cancer through the induction of both MAPK and PI3K signaling (Sizemore et al, 2007).…”

Section: Alteration In Adhesion Moleculessupporting

confidence: 84%

Broad and thematic remodeling of the surface glycoproteome on isogenic cells transformed with driving proliferative oncogenes

Leung¹,

Wilson

Kirkemo³

et al. 2019

Preprint

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The cell surface proteome, the surfaceome, is the interface for engaging the extracellular space in normal and cancer cells. Here we apply quantitative proteomics of N-linked glycoproteins to reveal how a collection of some 700 surface proteins is dramatically remodeled in an isogenic breast epithelial cell line stably expressing any of six of the most prominent proliferative oncogenes, including the receptor tyrosine kinases, EGFR and HER2, and downstream signaling partners such as KRAS, BRAF, MEK and AKT. We find that each oncogene has somewhat different surfaceomes but the functions of these proteins are harmonized by common biological themes including up-regulation of nutrient transporters, down-regulation of adhesion molecules and tumor suppressing phosphatases, and alteration in immune modulators. Addition of a potent MEK inhibitor that blocks MAPK signaling brings each oncogene-induced surfaceome back to a common state reflecting their strong dependence on the MAPK pathway to propagate signaling. Using a recently developed glyco-proteomics method of activated ion electron transfer dissociation (AI-ETD) we found massive oncogene-induced changes in 142 N-linked glycans and differential increases in complex hybrid glycans especially for KRAS and HER2 oncogenes. Overall, these studies provide a broad systems level view of how specific driver oncogenes remodel the surface glycoproteome in a cell autologous fashion, and suggest possible surface targets, and combinations thereof, for drug and biomarker discovery.

show abstract

Section: Alteration In Adhesion Moleculessupporting

confidence: 84%

Broad and thematic remodeling of the surface glycoproteome on isogenic cells transformed with driving proliferative oncogenes

Leung¹,

Wilson

Kirkemo³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Indeed, although our study confirmed via GSEA analysis that proteins in E0771 and PyMT‐WT exosomes do reflect cell of origin, specific sets of proteins are enriched in exosomes. For example, we noted that the MAPK signalling pathway appeared as a key biological process possibly involved in E0771 exosome function; a pathway known to be important in initiation of TGF‐β‐induced EMT . Various mechanisms have been implicated in the specific sorting of proteins into exosomes, including ESCRT (endosomal sorting complexes required for transport)‐dependent and independent systems, tetraspanins, and lipid‐dependent mechanisms .…”

Section: Discussionmentioning

confidence: 99%

Breast Cancer‐Derived Exosomes Reflect the Cell‐of‐Origin Phenotype

et al. 2019

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A manner in which cells can communicate with each other is via secreted nanoparticles termed exosomes. These vesicles contain lipids, nucleic acids, and proteins, and are said to reflect the cell‐of‐origin. However, for the exosomal protein content, there is limited evidence in the literature to verify this statement. Here, proteomic assessment combined with pathway‐enrichment analysis is used to demonstrate that the protein cargo of exosomes reflects the epithelial/mesenchymal phenotype of secreting breast cancer cells. Given that epithelial‐mesenchymal plasticity is known to implicate various stages of cancer progression, the results suggest that breast cancer subtypes with distinct epithelial and mesenchymal phenotypes may be distinguished by directly assessing the protein content of exosomes. Additionally, the work is a substantial step toward verifying the statement that cell‐derived exosomes reflect the phenotype of the cells‐of‐origin.

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“…Our data showed that 5‐FU, irinotecan and oxaliplatin, either when used alone or in typical combinations of FOLFOX and FOLFIRI, had variable and rather moderate effects on the frequency of tumor cells with high WNT and MAPK activity that we gauged through analyses of nuclear β‐catenin and FRA1, respectively. Such tumor cell subpopulations have previously been linked to tumor progression and were suggested to represent putative colon cancer stem cells . Our observations therefore imply that these tumor cell subsets are not specifically affected or targeted by typical chemotherapeutic protocols, and may therefore be responsible for tumor recurrence and therapy resistance .…”

Section: Discussionmentioning

confidence: 57%

In vivo effects of chemotherapy on oncogenic pathways in colorectal cancer

et al. 2019

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Patients with advanced colorectal cancer often are treated with systemic cytotoxic therapy using fluorouracil (5‐FU), oxaliplatin, irinotecan, and FOLFOX or FOLFIRI combination protocols. Additionally, signaling pathways that are active in colorectal cancer can be therapeutically targeted. Herein, we examined whether chemotherapy impacts on WNT, MAPK and NOTCH signaling pathways in xenograft models of colon cancer. Furthermore, we tested whether combining chemotherapy with MAPK and NOTCH inhibition has superior therapeutic effects. We show that colon cancer cells with high WNT, MAPK and NOTCH activity are variably affected but generally persist in xenograft tumors under different chemotherapeutic regimens, indicating limited effects of cytotoxic therapy on oncogenic signaling pathways. Although these results provided a rationale to additionally target pathway activity, we found no significant increase in therapy response when combining MAPK and NOTCH inhibition with fluorouracil chemotherapy. We attribute this finding to a decrease in tumor cell proliferation upon MAPK and NOTCH inhibition, resulting in reduced effectiveness of cytotoxic treatment. Therapeutic benefits of combining chemotherapy with targeting of oncogenic signaling pathways must therefore be critically evaluated for patients with colorectal cancer.

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Oncogenic Effects of High MAPK Activity in Colorectal Cancer Mark Progenitor Cells and Persist Irrespective of RAS Mutations

Cited by 62 publications

References 42 publications

Broad and thematic remodeling of the surface glycoproteome on isogenic cells transformed with driving proliferative oncogenes

Broad and thematic remodeling of the surface glycoproteome on isogenic cells transformed with driving proliferative oncogenes

Breast Cancer‐Derived Exosomes Reflect the Cell‐of‐Origin Phenotype

In vivo effects of chemotherapy on oncogenic pathways in colorectal cancer

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